Osmolyte-Induced Collapse of a Charged Macromolecule.

In the recent surge of investigations on osmolyte-induced conformational landscape of hydrophobic macromolecules notwithstanding, there is a lack of understanding of how the presence of Coulombic charges in the macromolecule dictates its own conformational preference in aqueous media of osmolyte. Toward this end, in this work, we have computationally simulated the trimethyl amine N-oxide (TMAO)-induced collapse behavior of a charge-neutral polymer by varying the number of oppositely charged monomeric beads of a given charge density. From our free-energy-based analysis, at low charge density, there emerges a nonmonotonic trend in the extent of osmolyte-induced protection of collapsed conformation of the charge-neutral polymer as a function of the number of periodically distributed charged monomers: specifically, we observe that, at low charge density, with incremental introduction of oppositely charged monomers in the charge-neutral polymer, the process of osmolyte-induced polymer collapse first gets free-energetically destabilized relative to that in uncharged polymer. However, with further increase in the number of charged monomers of low charge density, there is a recurrence of osmolyte-induced stabilization of polymer collapse. On the contrary, the nonmonotonic trend in osmolyte-induced polymer collapse across the number of charged monomer beads diminishes with an increase in charge density: the aqueous TMAO solution becomes a denaturant of the polymer collapse at higher charge distribution in charge-neutral polymer with higher charge density. A molecular-level analysis of the polymer-osmolyte interaction reveals that the differential interaction of nitrogen and oxygen atoms of TMAO with the charged polymer beads, together with the competing effect of polymer-TMAO dispersion interaction and electrostatic interaction, holds the key in dictating the trend in the osmolyte-induced protection of the polymer collapse across various charge densities and charge distributions.